The purpose of this invention is to provide a non-β-lactam mimic of the β-lactam antibiotics that target bacterial metabolic pathways; no analogous pathways are found in animals or plants. This is considered to be advantageous therapeutically because it minimizes interference(s) with the metabolism of the object of treatment.
The challenges to β-lactam antibiotics are increasing to the point that there is a fear that an unacceptably long list of pathogens may arise that are totally resistant to the pharmaceutically useful β-lactams as well as other antibiotics. See Thomson and Moland, Microbes and Infection 2, 1225–1236 (2000); Koch, Critical Rev. Microbiol. 26, 205–220 (2000); Emerging Drugs 5, 347–365 (2000); Kemodle, “Mechanisms of Resistance to β-Lactam Antibiotics” in Gram Positive Pathogens 609–620 (2000).
The last two decades have seen major changes in the types of β-lactamase production by which Gram-negative bacteria protect themselves from β-lactam antibiotics; this has occurred mainly by gene transfer and mutation. Changes have affected the responses to β-lactams in two significant ways; the production of novel β-lactamases with new substrate or β-lactamase inhibitor interactions, and the production of multiple β-lactamases. The result is an increasing number of pathogens, many of them nosocomial, with less predictable responses to β-lactam therapy, and which are sometimes not dependably indicated by routine antibiotic susceptibility tests. If laboratories do not detect new types of resistance, infected patients are put at risk. Some of the novel β-lactamases (the main cause of β-lactam resistance) have interchangeable chromosomal and plasmid-mediated genes; this promiscuity makes them capable of wide dissemination and confers the potential for epidemic problems. In some pathogens the effects of relatively weak β-lactamases may be augmented by other resistance mechanisms, producing synergistic effects in which the β-lactamases have a greater impact than anticipated. An increasing number of pathogens with a multiplicity of resistance mechanisms are appearing. This has created more multiple resistant, and sometimes totally resistant, pathogens. See Ahmad et al., Clin Infect. Dis. 29, 325–355 (1999). In a specific case the preferred use of carbapenems against Pseudomonas, runs the risk that resistance will develop against these useful β-lactams. See Livermore, J. Antimicrobial Chemotherapy 47, 247–250 (2001).
Novel important β-lactamases fall into four groups. These are 1) Extended spectrum β-lactamase (ESBLs), 2) β-lactamases with reduced sensitivity to β-lactamase inhibitors. 3) Plasmid-mediated AmpC β-lactamase, and 4) Carbapenem-hydrolyzing β-lactamases.
Increased bacterial resistance to β-lactams will continue to plague modem medicine. The unfortunate changes that have occurred in the types of β-lactamase production are themselves a consequence of the selection pressure created by antibiotic usage. Unpredictable responses of bacteria will undoubtedly continue to surprise us with increasing resistance to β-lactam antibiotics. See Livermore, op. cit. It seems inevitable that the most important threats to medicine will be more frequent encounters with pathogens that produce many β-lactamases including potent plasmid-mediated β-lactamases such as the extended spectrum β-lactamases, AmpC related β-lactamases, and metallo-β-lactamases. These β-lactams increase resistance. The latter are particularly alarming with their resistance to β-lactamase inhibitors in current pharmaceutical use. Also, all ESBLs are a challenge to β-lactam antibiotic usage. See Rahal, Clinical Microbiol. Infection 6 (suppl 2) 2–6 (2000). The inability of many clinical microbiology laboratories to provide timely and accurate information about the occurrence of such enzymes will further exacerbate their spread. In the face of all this, the spread of resistance will continue and there will be more bacteria that are resistant to currently available antibiotics. To avoid this it will be necessary to change current therapeutic and diagnostic approaches and to find novel antibiotics not affected by the increasing resistance to β-lactams.
A specific example of a major challenge to β-lactam antibiotics is the Gram T, resistant staphylococci. While the wild type staphylococci are susceptible to the β-lactans, they are an increasing source of morbidity and mortality in the nosocomial setting. Hospitals are plagued by resistant strains that represent a serious health hazard. See Livermore, International Journal of Antimicrobial Agents 16, S3–S10 (2000).